Carbostyril derivatives and serotonin reuptake inhibitors for treatment of mood disorders

ABSTRACT

The pharmaceutical composition of the present invention comprises (1) a carbostyril derivative and (2) a serotonin reuptake inhibitor in a pharmaceutically acceptable carrier. The carbostyril derivative may be aripiprazole or a metabolite thereof, which is a dopamine-serotonin system stabilizer. The serotonin reuptake inhibitor may be fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, fluvoxamine, paroxetine, sertraline or escitalopram. The pharmaceutical composition of the present invention is useful for treating patients with mood disorders, particularly depression or major depressive disorder.

TECHNICAL FIELD

The present invention provides pharmaceutical compositions comprisingcarbostyril derivatives that act as dopamine-serotonin systemstabilizers in combination with serotonin reuptake inhibitors in apharmaceutically acceptable carrier. Further, the present inventionprovides methods of using the compositions of the present invention totreat mood disorders such as depression and major depressive disorder.

BACKGROUND ART

The number of people with mood disorders such as major depressivedisorder, and exhibiting various symptoms of depressions is increasingevery year for numerous reasons such as social stress, unemployment,disease, and poverty. Depression is a major social problem throughoutthe world. For example, in Japan the occurrence rate of depression inthe generation older than 65 years is 5% or more, including majordepressive disorder. Some of the depression in this population isassociated with mental disturbances representing senile diseasesassociated with dementia and neurosis. Many depressed patients show highrecurrence rate, and severe depressive symptoms are major causes ofsuicide and drug abuse (Nishimura Ken, “NIPPON RONEN IGAKUZASSHI”, Vol.33, pp 503-504 (1996)).

Since the period of 1950, tricyclic antidepressant drugs (e.g.,imipramine, desipramine, amitriptyline, etc.) have been developed thatact to inhibit monoamine reuptake. They are frequently used for treatingpatients suffering from mood disorders, such as depression and majordepressive disorder. However, these drugs have side-effects such as thefollowing: dry mouth, hazy eyes, dysuria, constipation, recognitiondisturbance and the like due to anticholinergic activity; cardiovascularside-effects such as, orthostatic hypotension, tachycardia and the likeon the basis of α₁-adrenoreceptor antagonist activity; side-effects suchas, sedation, increase in the body weight and the like on the basis ofhistamine-H₁ receptor antagonist activity.

Since 1980, serotonin reuptake inhibitors have been developed, includingbut not limited to fluoxetine, duloxetine, venlafaxine, milnacipran,citalopram, escitalopram, fluvoxamine, paroxetine and sertraline, andthese inhibitors have side-effects such as recognition disturbance,sleep disturbance, and exacerbation of anxiety and agitation.Additionally, these inhibitors also have other side effects in thedigestive organs, such as nausea, vomiting and the like.

For the reason that the mood disorders such as depressive symptoms,depression and the like are diseases with severely strong psychalgalia,the manifestation of new symptoms on the basis of these side-effects arequite serious problems in the therapy of mood disorders (Shioe Kunihiko,Kariya Tetsuhiko, “SHINKEI SEISHIN YAKURI”, Vol. 11, pp 37-48 (1989);Yamada Mitsuhiko, Ueshima Kunitoshi, “RINSHOU SEISHIN YAKURI”, Vol. 1,pp 355-363 (1998)).

Although the mood disorders including depression and major depressivedisorder are heterogeneous diseases, and the causes of these diseasesare not been fully understood, it is likely that the abnormalities ofmonoaminergic central nervous system caused by serotonin, norepinephrineand dopamine and the like, and the abnormality of various hormones andpeptides as well as various stressors are causes of depression andvarious mood disorders (Kubota Masaharu et al., “RINSHOU SEISHIN IGAKU”,Vol. 29, pp 891-899 (2000)). For these reasons, even thoughantidepressant drugs, such as tricyclic antidepressants and serotoninreuptake inhibitors were used, these drugs are not always effective intreating all depressed patients. About 30% of the depressed patients donot respond to the primarily selected antidepressants (Nelson, J. C, etal., J. Clin. Psychiatry, 55, pp 12-19 (1994)). Further, when a secondor third antidepressant is administered to these patients, insufficientimprovements of the symptoms occurs in about 10% of these patients(Inoeu Takeshi, Koyama Tsukasa, “RINSHOU SEISHIN IGAKU”, Vol. 38, pp868-870 (1996)). These patients are called as refractory depressionpatients.

In some cases, electric shock therapy is used to treat refractorydepression, and the efficacy of this treatment has been reported.However, in fact, the condition of numerous patients is not improved(Inoue Takeshi, Koyama Tsukasa, “RINSHOU SEISHIN YAKURI”, Vol. 2, pp979-984 (1999)). Additionally, psychological anguish experienced bythese patients and their families concerning the use of the electricshock therapy can be severe.

New therapeutic trials involve proposed combined therapies using anatypical antipsychotic drug, such as olanzapine, which is an agent fortreating for schizophrenia (antipsychotic drug), together with anantidepressant drug such as serotonin reuptake inhibitor (EP 0 367 141,WO 98/11897, WO99/61027, WO99/62522, U.S. 2002/0123490A1 and the like).However, commercially available atypical antipsychotic drugs havesignificant problems relating to their safety. For example, clozapine,olanzapine and quetiapine increase body weight and enhance the risk ofdiabetes mellitus (Newcomer, J. W. (Supervised Translated by Aoba Anri),“RINSHOU SEISHIN YAKURI”, Vol. 5, pp 911-925 (2002); Haupt, D. W. andNewcomer, J. W (Translated by Fuji Yasuo and Misawa Fuminari), “RINSHOUSEISHIN YAKURI”, Vol. 5, pp 1063-1082 (2002)). In fact, urgent safetyalerts have been issued in Japan relating to hyperglycemia, diabeticketoacidosis and diabetic coma caused by olanzapine and quetiapine,indicating that these drugs were subjected to dosage contraindication tothe patients with diabetes mellitus and patients having anamnesis ofdiabetes mellitus. Risperidone causes increases serum prolactin levelsand produces extrapyramidal side effects at high dosages. Ziprasidoneenhances the risk of severe arrhythmia on the basis of cardio-QTcprolongation action. Further, clozapine induces agranulocytosis, so thatclinical use thereof is strictly restricted (van Kammen, D. P. (Compiledunder Supervision by Murasaki Mitsuroh), “RINSHOU SEISHIN YAKURI”, Vol.4, pp 483-492 (2001)).

Accordingly what is needed are new compositions useful for treating mooddisorders, particularly, depression and major depressive disorder, whichare efficacious and do not cause the deleterious side effects associatedwith prior art compounds.

DISCLOSURE OF THE INVENTION

The present invention solves the problem described above by providingnovel compositions and methods of using these compositions for treatingmood disorders, particularly depression and major depressive disorder.

The present invention provides solutions to the above-mentionedproblems, and demonstrates that the mood disorders such as depression,major depressive and the like can be treated effectively byadministering to a patient with such disorder a pharmaceuticalcomposition comprising at least one carbostyril derivative that is adopamine-serotonin system stabilizer in combination with at least oneserotonin reuptake inhibitor in a pharmaceutically acceptable carrier.

A preferred carbostyril derivative of the present invention that is adopamine-serotonin system stabilizer is aripiprazole or a metabolitethereof. Another preferred carbostyril derivative of the presentinvention that is a dopamine-serotonin system stabilizer is a metaboliteof aripiprazole called dehydroaripiprazole, also known as OPC-14857.Other such metabolites of aripiprazole included within the presentinvention are shown in FIG. 8. Preferred metabolites are shown in FIG. 8indicated by the following designations: OPC-14857, DM-1458, DM-1451,DM-1452, DM-1454 and DCPP.

Aripiprazole, also called7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone,is a carbostyril compound and is useful for treating schizophrenia (EP 0367 141, U.S. Pat. No. 5,006,528). Aripiprazole is also known as7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril,Abilify, OPC-14597, OPC-31 and BMS-337039. Aripiprazole possesses 5-HT1Areceptor agonist activity, and is known as useful compound for treatingtypes of depression and refractory depressions, such as endogeneousdepression, major depression, melancholia and the like (WO 02/060423, U.S. Patent Application 2002/0173513A1). Aripiprazole has activity as anagonist at the serotonin receptors and dopamine receptors, and acts asan agonist or partial agonist at the serotonin 5-HT1A receptor and as anagonist or partial agonist at the dopamine D₂ receptor. Aripiprazole isa dopamine-serotonin system stabilizer. Metabolites of aripiprazole areincluded within the scope of the present invention. One such metaboliteof aripiprazole is called dehydroaripiprazole. Other such metabolites ofaripiprazole included within the present invention are shown in FIG. 8.Preferred metabolites are shown in FIG. 8 indicated by the followingdesignations: OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454 and DCPP.

The at least one serotonin reuptake inhibitor used in the presentinvention includes but is not limited to the following: fluoxetine,duloxetine, venlafaxine, milnacipran, citalopram, fluvoxamine,paroxetine, sertraline, escitalopram and salts thereof. In a preferredembodiment, the pharmaceutical composition comprises aripiprazole andcitalopram in a pharmaceutically acceptable carrier.

The novel compositions of present invention comprising at least onecarbostyril derivative with activity as a dopamine-serotonin systemstabilizer and at least one serotonin reuptake inhibitor in apharmaceutically acceptable carrier may be combined in one dosage form,for example a pill. Alternatively the at least one carbostyrilderivative with activity as a dopamine-serotonin system stabilizer andthe at least one serotonin reuptake inhibitor may be in separate dosageforms, each in a pharmaceutically acceptable carrier. These compositionsare administered to a patient with a mood disorder, particularlydepression or major depressive disorder, in an amount and dosage regimeneffective to treat the mood disorder.

Accordingly, it is an object of the present invention to provide apharmaceutical composition useful for treating a mood disorder.

It is an object of the present invention to provide a composition usefulfor treating a mood disorder, wherein the mood disorder is depression ormajor depressive disorder.

It is another object of the present invention to provide a compositioncomprising at least one carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one serotonin reuptakeinhibitor in a pharmaceutically acceptable carrier.

Yet another object of the present invention is to provide a compositioncomprising at least one carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one serotonin reuptakeinhibitor in a pharmaceutically acceptable carrier, wherein thecarbostyril derivative is aripiprazole or a metabolite thereof.

Yet another object of the present invention is to provide a compositioncomprising at least one carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one serotonin reuptakeinhibitor in a pharmaceutically acceptable carrier, wherein thecarbostyril derivative is aripiprazole and the serotonin reuptakeinhibitor is citalopram.

Yet another object of the present invention is to provide a compositioncomprising at least one carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one serotonin reuptakeinhibitor, wherein the carbostyril derivative with activity as adopamine-serotonin system stabilizer is a metabolite of aripiprazole andis dehydroaripiprazole (OPC-14857), DM-1458, DM-1451, DM-1452, DM-1454or DCPP.

Yet another object of the present invention is to provide a compositioncomprising at least one carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one serotonin reuptakeinhibitor, wherein the carbostyril derivative is dehydroaripiprazole.

It is an object of the present invention to provide a use of acomposition useful for treating a mood disorder in the preparation of amedicament for treatment of a mood disorder, wherein the mood disorderis depression or major depressive disorder.

It is another object of the present invention to provide a use of acomposition comprising at least one carbostyril derivative with activityas a dopamine-serotonin system stabilizer and at least one serotoninreuptake inhibitor in a pharmaceutically acceptable carrier in thepreparation of a medicament for treatment of a mood disorder.

Yet another object of the present invention is to provide a use of acomposition comprising a carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one serotonin reuptakeinhibitor in a pharmaceutically acceptable carrier in the preparation ofa medicament for treatment of mood disorders, wherein the carbostyrilderivative is aripiprazole or a metabolite thereof.

Yet another object of the present invention is to provide a use of acomposition comprising a carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one serotonin reuptakeinhibitor in a pharmaceutically acceptable carrier in the preparation ofa medicament for treatment of mood disorders, wherein at least onecarbostyril derivative is aripiprazole and at least one serotoninreuptake inhibitor is citalopram.

Yet another object of the present invention is to provide a use of acomposition comprising at least one carbostyril derivative with activityas a dopamine-serotonin system stabilizer and at least one serotoninreuptake inhibitor pharmaceutically acceptable carrier in thepreparation of a medicament for treatment of mood disorders, wherein thecarbostyril derivative with activity as a dopamine-serotonin systemstabilizer is a metabolite of aripiprazole and is dehydroaripiprazole(OPC-14857), DM-1458, DM-1451, DM-1452, DM-1454 or DCPP.

Yet another object of the present invention is to provide a use of acomposition comprising a carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one serotonin reuptakeinhibitor in a pharmaceutically acceptable carrier in the preparation ofa medicament for treatment of mood disorders, wherein the carbostyrilderivative is dehydroaripiprazole.

It is an object of the present invention to provide a method fortreating a mood disorder.

It is an object of the present invention to provide a method fortreating a mood disorder wherein the mood disorder is depression ormajor depressive disorder.

It is another object of the present invention to provide a method fortreating a mood disorder comprising administration to a patient with amood disorder of a composition comprising at least one carbostyrilderivative with activity as a dopamine-serotonin system stabilizer andat least one serotonin reuptake inhibitor in a pharmaceuticallyacceptable carrier.

It is another object of the present invention to provide a method fortreating a mood disorder comprising administration to a patient with amood disorder of a composition comprising at least one carbostyrilderivative with activity as a dopamine-serotonin system stabilizer andat least one serotonin reuptake inhibitor together in a pharmaceuticallyacceptable carrier, wherein the carbostyril derivative is aripiprazoleor a metabolite thereof.

It is another object of the present invention to provide a method fortreating major depressive disorder comprising administration to apatient with major depressive disorder of a composition comprising acarbostyril derivative with activity as a dopamine-serotonin systemstabilizer and at least one serotonin reuptake inhibitor together with apharmaceutically acceptable carrier, wherein the carbostyril derivativeis aripiprazole and the serotonin reuptake inhibitor is citalopram.

Still another object of the present invention is to provide a method fortreating a mood disorder comprising administration to a patient with amood disorder of a composition comprising at least one carbostyrilderivative with activity as a dopamine-serotonin system stabilizer andat least one serotonin reuptake inhibitor in a pharmaceuticallyacceptable carrier, wherein the carbostyril derivative is a metaboliteof aripiprazole and is dehydroaripiprazole (OPC-14857), DM-1458,DM-1451, DM-1452, DM-1454 or DCPP.

Yet another object of the present invention is to provide a method fortreating major depressive disorder comprising administration to apatient with major depressive disorder of a composition comprising atleast one carbostyril derivative with activity as a dopamine-serotoninsystem stabilizer and at least one serotonin reuptake inhibitor in apharmaceutically acceptable carrier, wherein the mood disorder is majordepressive disorder.

It is another object of the present invention to provide a method fortreating major depressive disorder comprising administration to apatient with major depressive disorder of a composition comprising atleast one carbostyril derivative with activity as a dopamine-serotoninsystem stabilizer and at least one serotonin reuptake inhibitor in apharmaceutically acceptable carrier.

It is another object of the present invention to provide a method fortreating major depressive disorder comprising administration to apatient with major depressive disorder of a composition comprising atleast one carbostyril derivative with activity as a dopamine-serotoninsystem stabilizer and at least one serotonin reuptake inhibitor togetherwith a pharmaceutically acceptable carrier, wherein the carbostyrilderivative is aripiprazole or a metabolite thereof.

Still another object of the present invention is to provide a method fortreating major depressive disorder comprising administration to apatient with major depressive disorder of a composition comprising atleast one carbostyril derivative with activity as a dopamine-serotoninsystem stabilizer and at least one serotonin reuptake inhibitor in apharmaceutically acceptable carrier, wherein the carbostyril derivativeis a metabolite of aripiprazole and is dehydroaripiprazole (OPC-14857),DM-1458, DM-1451, DM-1452, DM-1454 or DCPP.

These and other objects, advantages, and uses of the present inventionwill reveal themselves to one of ordinary skill in the art after readingthe detailed description of the preferred embodiments and the attachedclaims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is the thermogravimetric/differential thermogram of thearipiprazole hydrate A obtained in Reference Example 4.

FIG. 2 is the ¹H-NMR spectrum (DMSO-d₆, TMS) of the aripiprazole hydrateA obtained in Reference Example 4.

FIG. 3 is the powder X-ray diffraction diagram of the aripiprazolehydrate A obtained in Reference Example 4.

FIG. 4 is the ¹H-NMR spectrum (DMSO-d₆, TMS) of the AnhydrousAripiprazole Crystals B obtained in Example 1.

FIG. 5 is the powder X-ray diffraction diagram of the AnhydrousAripiprazole Crystals B obtained in Example 1.

FIG. 6 is the thermogravimetric/differential thermogram of thearipiprazole hydrate A obtained in Reference Example 3.

FIG. 7 is the powder X-ray diffraction diagram of aripiprazole hydrateobtained in Reference Example 3.

FIG. 8 is a schematic representation of the chemical structures ofaripiprazole and metabolites thereof. Some of the metabolites may beformed through other possible pathways; for example, DM-1431 could beformed by N-dealkylation of DM-1451 and DM-1459.

DETAILED DESCRIPTION OF THE INVENTION

The pharmaceutical composition of the present invention comprises afirst ingredient comprising a carbostyril derivative active as adopamine-serotonin system stabilizer and a second ingredient comprisinga serotonin reuptake inhibitor, in a pharmaceutically acceptablecarrier. The pharmaceutical compositions of the present invention areuseful in treating mood disorders, including depression and majordepressive disorder.

The Pharmaceutical Composition: The First Ingredient

The first ingredient comprises a carbostyril derivative active as adopamine-serotonin system stabilizer. Such carbostyril derivative hasactivity as an agonist or partial agonist at some serotonin receptorsand some dopamine receptors, preferably as an agonist or partial agonistat the serotonin 5-HT1A receptor and as an agonist or partial agonist atthe dopamine D₂ receptor. Carbostyril derivatives are described in U.S.Pat. No. 5,006,528 and U.S. published patent application 2002/0173513A1.In one embodiment of the present invention, the carbostyril derivativesrepresented by the following formula (1) are used:

wherein the carbon-carbon bond between 3- and 4-positions in thecarbostyril skeleton is a single or a double bond.

In a preferred embodiment, this activity of the carbostyril derivativeis as an agonist or partial agonist at the 5-HT1A receptor and anagonist or partial agonist at the dopamine D₂ receptor subtype. Inanother preferred embodiment, the carbostyril derivative to be used as afirst component in the present invention is aripiprazole, or a metabolicderivative thereof. Metabolic derivatives of aripiprazole include butare not limited to dehydroaripiprazole, also called OPC-14857. Othermetabolic derivatives of aripiprazole include but are not limited to thechemical structures shown in FIG. 8 as OPC-14857, DM-1458, DM-1451,DM-1452, DM-1454 and DCPP. All of the aforementioned carbostyrilderivatives may be used as a first component in the practice of thepresent invention.

Aripiprazole, also called7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone,is a carbostyril compound useful as the effective ingredient fortreating schizophrenia (JP-A-2-191256, U.S. Pat. No. 5,006,528).Aripiprazole is also known as7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril,Abilify, OPC-14597, OPC-31 and BMS-337039. Aripiprazole possesses 5-HT1Areceptor agonist activity, and is known as a useful compound fortreating types of depression and refractory depression, such asendogenous depression, major depression, melancholia and the like (WO02/060423A2; Jordan et al. U.S. Patent Application 2002/0173513A1).Aripiprazole has activity as an agonist at serotonin receptors anddopamine receptors, and acts as an agonist or partial agonist at theserotonin 5-HT1A receptor and as an agonist or partial agonist at thedopamine D₂ receptor.

Aripiprazole is an antipsychotic drug having new mechanism of actionwhich is different from that of other atypical antipsychotic drugs(Grunder, G. et al., Arch Gen Psychiatry, 60(10), pp 974-977, 2003). Theavailable typical and atypical antipsychotic drugs act as antagonists atthe dopamine-D₂ receptors. In contrast, aripiprazole acts as a partialagonist at the dopamine D₂ receptor (By Ishigooka Jyunya and Inada Ken,RINSHO SEISHIN YAKURI, Vol. 4, pp 1653-1664 (2001); Burris, K. D. etal., J. Pharmacol. Exp. Ther., 302, pp 381-389 (2002)). In addition tothe partial agonist action at dopamine-D₂ receptors, aripiprazole hasactivity as a partial agonist at the serotonin 5-HT1A receptors, as wellas antagonist action at serotonin 5-HT2A receptors. Accordingly,aripiprazole is a drug belonging to new category defined as adopamine-serotonin system stabilizer (dopamine-serotonin stabilizer(Burris, K. D. et al., J. Pharmacol, Exp. Ther., 302, pp 381-389, 2002;Jordan, S. et al., Eur. J. Pharmacol. 441, pp 137-140, 2002; Grunder, G.et al., Arch Gen Psychiatry, 60(10), pp 974-977, 2003).

Methods of Preparing Aripiprazole

Aripiprazole and aripiprazole metabolites to be used in the presentinvention may be any of form, for example, free bases, polymorphisms ofevery type of crystal, hydrate, salts (acid addition salts, etc.) andthe like. Among of these forms, Anhydrous Aripiprazole Crystals B is apreferred form.

As to method for preparing the Anhydrous Aripiprazole Crystals B, forexample it is prepared by heating aripiprazole hydrate A as follows.

Aripiprazole Hydrate A

The aripiprazole hydrate A having the physicochemical properties shownin (1)-(5) as follows:

(1) It has an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate 5° C./min)endothermic curve shown in FIG. 1. Specifically, it is characterized bythe appearance of a small peak at about 71° C. and a gradual endothermicpeak around 60° C. to 120° C.

(2) It has an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 2. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

(3) It has a powder x-ray diffraction spectrum which is substantiallyidentical to the powder x-ray diffraction spectrum shown in FIG. 3.Specifically, it has characteristic peaks at 2θ=12.6°, 15.4°, 17.3°,18.0°, 18.6°, 22.5° and 24.8°.

(4) It has clear infrared absorption bands at 2951, 2822, 1692, 1577,1447, 1378, 1187, 963 and 784 cm⁻¹ on the IR (KBr) spectrum.

(5) It has a mean particle size of 50 μm or less.

Method for Preparing Aripiprazole Hydrate A

Aripiprazole hydrate A is prepared by milling conventional aripiprazolehydrate. Conventional milling methods can be used to mill conventionalaripiprazole hydrate. For example, conventional aripiprazole hydrate canbe milled in a milling machine. A widely used milling machine such as anatomizer, pin mill, jet mill or ball mill can be used. Among of these,the atomizer is preferably used.

Regarding the specific milling conditions when using an atomizer, arotational speed of 5000-15000 rpm could be used for the main axis, forexample, with a feed rotation of 10-30 rpm and a screen hole size of 1-5mm.

The mean particle size of the aripiprazole hydrate A obtained by millingmay be normally 50 μm or less, preferably 30 μm or less. Mean particlesize can be ascertained by the particle size measuring method describedhereinafter.

Anhydrous Aripiprazole Crystals B

“Anhydrous Aripiprazole Crystals B” of the present invention have thephysicochemical properties given in (6)-(10) below.

(6) They have an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 4. Specifically, they havecharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

(7) They have a powder x-ray diffraction spectrum which is substantiallyidentical to the powder x-ray diffraction spectrum shown in FIG. 5.Specifically, they have characteristic peaks at 2θ=11.0°, 16.6°, 19.3°,20.3° and 22.1°.

(8) They have clear infrared absorption bands at 2945, 2812, 1678, 1627,1448, 1377, 1173, 960 and 779 cm⁻¹ on the IR (KBr) spectrum.

(9) They exhibit an endothermic peak near about 141.5° C. inthermogravimetric/differential thermal analysis (heating rate 5°C./min).

(10) They exhibit an endothermic peak near about 140.7° C. indifferential scanning calorimetry (heating rate 5° C./min).

When the small particle size is required for solid preparation, such astablets and other solid dose formulations including for example flashmelt formulations, the mean particle size is preferably 50 μm or less.

Method for Preparing Anhydrous Aripiprazole Crystals B

The Anhydrous Aripiprazole Crystals B of the present invention areprepared for example by heating the aforementioned aripiprazole hydrateA at 90-125° C. The heating time is generally about 3-50 hours, butcannot be stated unconditionally, because it differs depending onheating temperature. The heating time and heating temperature areinversely related, so that for example when the heating time is longer,then the heating temperature is lower, and when the heating temperatureis higher then the heating time is shorter. Specifically, if the heatingtemperature of aripiprazole hydrate A is 100° C., the heating time maybe 18 hours or more, or preferably about 24 hours. If the heatingtemperature of aripiprazole hydrate A is 120° C., on the other hand, theheating time may be about 3 hours. The Anhydrous Aripiprazole Crystals Bof the present invention can be prepared with certainty by heatingaripiprazole hydrate A for about 18 hours at 100° C., and then heatingit for about 3 hours at 120° C. The Anhydrous Aripiprazole Crystals B ofthe present invention can also be obtained if the heating time isextended still further, but this method may not be economical.

When small particle size is not required for the formulation, e.g., whendrug substance is being prepared for injectable or oral solutionformulations, Anhydrous Aripiprazole Crystals B can be also obtained bythe following process.

Anhydrous Aripiprazole Crystals B of the present invention are preparedfor example by heating conventional anhydrous aripiprazole crystals at90-125° C. The heating time is generally about 3-50 hours, but cannot bestated unconditionally because it differs depending on heatingtemperature. The heating time and heating temperature are inverselyrelated, so that for example if the heating time is longer, the heatingtemperature is lower, and if the heating time is shorter, the heatingtemperature is higher. Specifically, if the heating temperature of theanhydrous aripiprazole crystals is 100° C., the heating time may beabout 4 hours, and if the heating temperature is 120° C. the heatingtime may be about 3 hours.

Furthermore, Anhydrous Aripiprazole Crystals B of the present inventionare prepared for example, by heating conventional aripiprazole hydrateat 90-125° C. The heating time is generally about 3-50 hours, but cannotbe stated unconditionally because it differs depending on heatingtemperature. The heating time and heating temperature are inverselyrelated, so that for example, if the heating time is longer, the heatingtemperature is lower, and if the heating time is shorter, the heatingtemperature is higher. Specifically, if the heating temperature of thearipiprazole hydrate is 100° C., the heating time may be about 24 hours,and if the heating temperature is 120° C. the heating time may be about3 hours.

The anhydrous aripiprazole crystals which are the raw material forpreparing the Anhydrous Aripiprazole Crystals B of the present inventionare prepared for example by Method a or b below.

“Method a”: Process for Preparing Crude Crystals of Aripiprazole

Conventional anhydrous aripiprazole crystals are prepared by well-knownmethods, as described in Example 1 of Japanese Unexamined PatentPublication No. 191256/1990.

7-(4-bromobutoxy)-3,4-dihydrocarbostyril, is reacted with1-(2,3-dichlorophenyl)piperazine and the thus obtained crudearipiprazole crystals are recrystallized from ethanol.

“Method b”: Process for Preparing Conventional Anhydrous Aripiprazole

The Method b is described in the Proceedings of the 4th JointJapanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996).

The aripiprazole hydrate which is the raw material for preparing theAnhydrous Aripiprazole Crystals B of the present invention is preparedfor example by Method c below.

“Method c”: Method for Preparing Conventional Aripiprazole Hydrate

Aripiprazole hydrate is easily obtained by dissolving the anhydrousaripiprazole crystals obtained by Method a above in a hydrous solvent,and heating and then cooling the resulting solution. Using this method,aripiprazole hydrate is precipitated as crystals in the hydrous solvent.

An organic solvent containing water is usually used as the hydroussolvent. The organic solvent may be preferable one which is misciblewith water, for example an alcohol such as methanol, ethanol, propanolor isopropanol, a ketone such as acetone, an ether such astetrahydrofuran, dimethylformamide, or a mixture thereof, ethanol isparticularly desirable. The amount of water in the hydrous solvent maybe 10-25% by volume of the solvent, or preferably close to 20% byvolume.

Aripiprazole can easily form an acid addition salt with apharmaceutically acceptable acid. As to such acid, for example, aninorganic acid, such as sulfuric acid, nitric acid, hydrochloric acid,phosphoric acid, hydrobromic acid, etc.; an organic acid such as, aceticacid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, maleicacid, fumaric acid, malic acid, tartaric acid, citric acid, benzoicacid, succinic acid, etc. can be exemplified. Similar to aripiprazole offree forms, these acid addition salts can also be used as the activeingredient compounds in the present invention.

The objective compound thus obtained through each one of productionsteps, is separated from the reaction system by usual separation means,and can be further purified. As to the separation and purificationmeans, for example, distillation method, solvent extraction method,dilution method, recrystallization method, column chromatography,ion-exchange chromatography, gel chromatography, affinitychromatography, preparative thin-layer chromatography and the like canbe exemplified.

The Pharmaceutical Composition: The Second Ingredient

In the composition of the present invention, a serotonin reuptakeinhibitor is used as the second ingredient. Compounds which function asserotonin reuptake inhibitors can be widely used as the serotoninreuptake inhibitors and are known to one of ordinary skill in the art.

Among the serotonin reuptake inhibitors, those having IC₅₀ value (aconcentration of the drug that inhibits serotonin reuptake by about50%), measured by the method of Wong et al. (Neuropsychopharmacology, 8,pp 337-344 (1993)), the standard pharmacological assay method, is about1000 nM or lower is preferable.

As to such serotonin reuptake inhibitors, for example, fluvoxamine(5-methoxy-1-[4-(trifluoro-methyl)phenyl]-1-pentanone-O-(2-aminoethyl)oxime),fluoxetine (N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine),paroxetine(trans-(−)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-piperidine),sertraline(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylylaminehydrochloride), venlafaxine, milnacipran(N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxyamide),citalopram, escitalopram, duloxetine and the like may be used.

The serotonin reuptake inhibitor may be either in the form of a freebase or a salt (an acid addition salt or the like). Further, theserotonin reuptake inhibitor may be either a racemic modifications or Rand S enantiomers.

The serotonin reuptake inhibitors may be either a single use of oneserotonin reuptake inhibitor, and in case of need, two or more of theserotonin reuptake inhibitors may be used in combination. Use of oneserotonin reuptake inhibitor is preferred.

The serotonin reuptake inhibitor can easily form an acid addition saltwith a pharmaceutically acceptable acid. As to such acid, for example,an inorganic acid, such as sulfuric acid, nitric acid, hydrochloricacid, phosphoric acid, hydrobromic acid, etc.; an organic acid such as,acetic acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid,maleic acid, fumaric acid, malic acid, tartaric acid, citric acid,benzoic acid, succinic acid, etc. can be exemplified. Similar to thereuptake inhibitor of free forms, these acid addition salts can be alsoused as the active ingredient compounds in the present invention.

Among the serotonin reuptake inhibitors, a compound having acidic groupcan easily form salt by reacting with a pharmaceutically acceptablebasic compound. As to such basic compound, a metal hydroxide, forexample, sodium hydroxide, potassium hydroxide, lithium hydroxide,calcium hydroxide and the like; an alkali metal carbonate orbicarbonate, for example sodium carbonate, potassium carbonate, sodiumhydrogencabonate, potassium hydrogencarbonate and the like; a metalalcoholate, for example sodium methylate, potassium ethylate and thelike can be exemplified.

The thus obtained salt form of serotonin reuptake inhibitor is separatedfrom the reaction system by usual separation means, and can be furtherpurified. As to the separation and purification means, for example,distillation method, solvent extraction method, dilution method,recrystallization method, column chromatography, ion-exchangechromatography, gel chromatography, affinity chromatography, preparativethin-layer chromatography and the like can be exemplified.

Combination of the First Ingredient with the Second Ingredient

As to combination of carbostyril derivatives with activity asdopamine-serotonin system stabilizers, non-limiting examples ofaripiprazole and dehydroaripiprazole are described herein. Whenaripiprazole is combined with at least one serotonin reuptake inhibitor,the following are non-limiting examples of such combinations:aripiprazole/fluoxetine, aripiprazole/duloxetine,aripiprazole/venlafaxine, aripiprazole/milnacipran,aripiprazole/citalopram, aripiprazole/fluvoxamine,aripiprazole/paroxetine, and aripiprazole/sertraline. A preferredembodiment comprises a combination of aripiprazole/citalopram.

In another embodiment of the present invention, aripiprazole, or ametabolite thereof may be combined with more than one serotonin reuptakeinhibitor. Metabolites of aripiprazole that may be used in the presentinvention include but are not limited to OPC-14857, DM-1458, DM-1451,DM-1452, DM-1454 and DCPP as shown in FIG. 8. Any one of thesemetabolites may be used in the present invention. The followingsentences describe a combination of dehydroaripiprazole with specificserotonin reuptake inhibitors, however it is to be understood that anyone of DM-1458, DM-1451, DM-1452, DM-1454 or DCPP, as shown in FIG. 8,could be substituted for dehydroaripiprazole in these disclosedcombinations. Dehydroaripiprazole (also called OPC-14857 in FIG. 8) is apreferred metabolite of aripiprazole. As to combination ofdehydroaripiprazole with serotonin reuptake inhibitor, the following arenon-limiting examples of such combinations:dehydroaripiprazole/fluoxetine, dehydroaripiprazole/duloxetine,dehydroaripiprazole/venlafaxine, dehydroaripiprazole/milnacipran,dehydroaripiprazole/citalopram, dehydroaripiprazole/fluvoxamine,dehydroaripiprazole/paroxetine, and dehydroaripiprazole/sertraline. Apreferred embodiment comprises a combination of dehydroaripiprazole andcitalopram.

Method of Treating a Mood Disorder, Especially Major Depressive Disorder

Patients with mood disorders may be treated with the compositions of thepresent invention. A preferred disorder treated with the method andcompositions of the present invention is depression or major depressivedisorder. Treatment comprises administration of the compositions of thepresent invention to a patient with a mood disorder such as depressionor major depressive disorder, in an amount and dose regimen effective totreat the mood disorder.

Dosage

Dosage of the drug used in the present invention is decided byconsidering the properties of each constituting drug to be combined, theproperties of drugs being after combination and symptoms of the patient(existence of other diseases beside mood disorders such as depression ormajor depressive disorder). General outlines of the dosage can beapplied the following guidelines.

Aripiprazole or a metabolite, such as dehydroaripiprazole, DM-1458,DM-1451, DM-1452, DM-1454 or DCPP: generally about 0.1 to 100 mg/once aday (or about 0.05 to about 50 mg/twice a day), preferably about 1 to 30mg/once a day (or about 0.5 to about 15 mg/twice a day).

The aripiprazole, or a metabolite thereof, may be combined with at leastone of any of the following SRIs at the dosage ranges indicated:

Fluoxetine: generally about 1 to about 80 mg/once a day, preferablyabout 10 to about 40 mg/once a day;

Duloxetine: generally about 1 to 160 mg/once a day (or 80 mg/twice aday), preferably about 5 to about 20 mg/once a day;

Venlafaxine: generally about 10 to 150 mg/l to 3 times a day, preferablyabout 25 to 125 mg/3 times a day;

Milnacipran: generally about 10 to 100 mg/l to 2 times a day, preferablyabout 25 to about 50 mg/twice a day;

Citalopram: generally about 5 to about 50 mg/once a day, preferablyabout 10 to about 30 mg/once a day;

Escitalopram: generally about 5 to about 30 mg/once a day, preferablyabout 10 to about 20 mg/once a day;

Fluvoxamine: generally about 20 to 500 mg/once a day, preferably about50 to 300 mg/once a day;

Paroxetine: generally about 20 to about 50 mg/once a day, preferablyabout 20 to about 30 mg/once a day; or

Sertraline: generally, about 20 to about 500 mg/once a day, preferablyabout 50 to about 200 mg/once a day.

Generally, the weight ratio of the first ingredient to the secondingredient is selected in accordance with the above-mentioned guideline.As to the ratio of the first ingredient and the second ingredient, ifthe first ingredient is about 1 part by weight of the former, the secondingredient is used about 0.01 to about 500 parts by weight, preferablyabout 0.1 to about 100 parts by weight.

Pharmaceutically Acceptable Carriers

Pharmaceutically acceptable carriers include diluents and excipientsgenerally used in pharmaceutical preparations, such as fillers,extenders, binders, moisturizers, disintegrators, surfactant, andlubricants.

The pharmaceutical composition of the present invention may beformulated as an ordinary pharmaceutical preparation, for example in theform of tablets, flash melt tablets, pills, powder, liquid, suspension,emulsion, granules, capsules, suppositories or injection (liquid,suspension, etc.), troches, intranasal spray percutaneous patch and thelike.

In case of shaping to tablet formulation, a wide variety of carriersthat are known in this field can be used. Examples include lactose,saccharose, sodium chloride, glucose, urea, starch, xylitol, mannitol,erythritol, sorbitol, calcium carbonate, kaolin, crystalline cellulose,silic acid and other excipients; water, ethanol, propanol, simple syrup,glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dried starch, sodium alginate, agarpowder, laminaran powder, sodium hydrogencarbonate, calcium carbonate,polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate,stearic acid monoglyceride, starch, lactose and other disintegrators;white sugar, stearin, cacao butter, hydrogenated oil and otherdisintegration inhibitors; quaternary ammonium salt, sodium laurylsulfate and other absorption accelerator; glycerine, starch and othermoisture retainers; starch, lactose, kaolin, bentonite, colloidal silicacid and other adsorbents; and refined talc, stearate, boric acidpowder, polyethylene glycol and other lubricants and the like. Tabletscan also be formulated if necessary as tablets with ordinary coatings,such as sugar-coated tablets, gelatin-coated tablets, enteric coatedtablets and film coated tablets, as well as double tablets andmultilayered tablets.

In case of shaping to pills, a wide variety of carriers that are knownin this field can be used. Examples include glucose, lactose, starch,cacao butter, hardened vegetable oil, kaolin, talc and other excipients;gum arabic powder, traganth powder, gelatin, ethanol and other binders;and laminaran, agar and other disintegrators and the like.

In case of shaping to a suppository formulation, a wide variety ofcarriers that are known in the field can be used. Examples includepolyethylene glycol, cacao butter, higher alcohol, esters of higheralcohol, gelatin semi-synthetic glyceride and the like.

Capsules are prepared according to ordinary methods by mixingcarbostyril derivatives such as anhydrous aripiprazole crystals as thefirst ingredient and serotonin reuptake inhibitor as the secondingredient, and the various carriers described above and packing them inhard gelatin capsules, soft capsules hydroxypropylmethyl cellulosecapsules (HPMC capsules) and the like.

In addition, colorants, preservatives, perfumes, flavorings, sweetenersand the like as well as other drugs may be contained in thepharmaceutical composition.

The amounts of the first ingredient and the second ingredient to becontained in the pharmaceutical composition of the present invention aresuitably selected from a wide range depending on the diseases to betreated. Generally, about 1 to 70 parts by weight, preferably about 1 to30 parts by weight of the first ingredient and the second ingredient inthe total amount on the basis of the pharmaceutical composition.

The methods for administration of the pharmaceutical composition of thepresent invention are not specifically restricted. The composition isadministered depending on each type of preparation forms, and the age,gender and other condition of the patient (degree and conditions of thedisease, etc.). For example, tablets, pills, liquids, suspensions,emulsions, granules and capsules are administered orally. In case ofinjection preparation, it is administered intravenously by either singlyor mixed with a common auxiliary liquid such as solutions of glucose oramino acid. Further, if necessary, the injection preparation is singlyadministered intracutaneously, subcutaneously or intraperitoneally. Incase of a suppository, it is administered intrarectally.

Administration forms of the pharmaceutical composition of the presentinvention may be any type by which the effective levels of bothcarbostyril derivatives and serotonin reuptake inhibitors can be providein vivo at the same time. In one embodiment, a carbostyril derivativetogether with a serotonin reuptake inhibitor are contained in onepharmaceutical composition and this composition may be administered. Onthe other hand, each one of carbostyril derivative and a serotoninreuptake inhibitor are contained individually in a pharmaceuticalpreparation respectively, and each one of these preparations may beadministered at the same time or in suitable intervals.

Dosage of the pharmaceutical composition of the present invention fortreating and improving depression or major depressive disorder may beused relatively in a small amount, because the composition possessesexcellent efficacy. Therefore the composition has fewer side-effects andan excellent safety profile.

The pharmaceutical composition of the present invention is quiteeffective for treating or improving mood disorders such as depressivesymptoms, depression, refractory depression, major depressive disorderand the like.

The pharmaceutical composition of the present invention can be manifestin a wide range of neurotransmission accommodation actions. As a result,the composition of the present invention establishes pseudo-homeostaticdopaminergic and serotoninergic neurotransmission (as a result ofpartial agonism), which, as a result of neuropathophysiologicalprocesses has ceased to function normally.

The mood disorders which can be treated by the pharmaceuticalcomposition of the present invention includes the mood disorders beingclassified in “Diagnostic and Statistical Manual of Mental Disorders”Fourth Edition (DSM-IV) published by the American PsychiatricAssociation. These mood disorders include, for example, major depressivedisorder, all mood disorders, schizoaffective disorder, dementia withdepressive symptoms and the like. A preferred disorder to be treatedwith the present invention is major depressive disorder.

The pharmaceutical composition of the present invention is useful fortreating major depressive disorder, endogenous depression, melancholia,depression in combination with psychotic episodes, bipolar disorder withdepressive phase, refractory depression, dementia of the Alzheimer'stype with depressive symptoms, Parkinson's disease with depressivesymptom, senile dementia, mood disorder associated with cerebral bloodvessels and mood disorder following head injury and the like. Inaddition to the methods for treatment described herein, additionaldisclosure for designing clinical studies is provided in J. Clin.Psychiatry, 2002, 63:(12), pp 1164-1170; J. Clin. Psychiatry, 2002,63:(8), pp 733-736; and J. Clin. Psychiatry, 2002, 63:(5), pp 391-395.

EXAMPLES

The present invention will be explained more in detail by illustratingReference Examples, Example and Formulation Sample Examples. First,analytical methods are explained.

Analytical Methods

(1) The ¹H-NMR spectrum was measured in DMSO-d₆ by using TMS as thestandard.

(2) Powder X-ray Diffraction

By using RAD-2B diffraction meter manufactured by Rigaku Denki, thepowder x-ray diffraction pattern was measured at room temperature byusing a Cu Ka filled tube (35 kV 20 mA) as the x-ray source with awide-angle goniometer, a 1° scattering slit, an 0.15 mmlight-intercepting slit, a graphite secondary monochromator and ascintillation counter. Data collection was done in 2θ-continuous scanmode at a scan speed of 5°/minute in scan steps of 0.02° in the range of3° to 40°.

(3) The IR spectrum was measured by the KBr method.

(4) Thermogravimetric/Differential Thermal Analysis

Thermogravimetric/differential thermal analysis was measured by usingSSC 5200 control unit and TG/DTA 220 simultaneous differentialthermal/thermogravimetric measuring unit manufactured by Seiko Corp.Samples (5-10 mg) were placed in open aluminum pans and heated at from20° C. to 200° C. in a dry nitrogen atmosphere at a heating rate of 5°C./minute. α-Alumina was used as the standard substance.

(5) Differential Scanning calorimetry

Thermogravimetric/differential thermal analysis was measured by usingSSC 5200 control unit and DSC 220C differential scanning calorimetermanufactured by Seiko Corp. Samples (5-10 mg) were placed in crimpedaluminum pans and heated from 20° C. to 200° C. in a dry nitrogenatmosphere at a heating rate of 5° C./minute. α-Alumina was used as thestandard substance.

(6) Particle Size Measurement

The particles (0.1 g) to be measured were suspended in a 20 ml n-hexanesolution of 0.5 g soy lecithin, and particle size was manufactured byusing a size distribution measuring meter (Microtrack HRA, manufacturedby Microtrack Co.).

Reference Example 1

7-(4-Cholorobutoxy)-3,4-dihydrocarbostyril (19.4 g) andmonohydrochloride 16.2 g of 1-(2,3-dichlorophenyl)piperadine 1hydrochloride were added to a solution of 8.39 g of potassium carbonatedissolved in 140 ml of water, and refluxed for 3 hours under agitation.After the reaction was complete, the mixture was cooled and theprecipitated crystals collected by filtration. These crystals weredissolved in 350 ml of ethyl acetate, and about 210 ml of water/ethylacetate azeotrope was removed under reflux. The remaining solution wascooled, and the precipitated crystals were collected by filtration. Theresulting crystals were dried at 60° C. for 14 hours to obtain 20.4 g(74.2%) of crude product of aripiprazole.

The crude product of aripiprazole (30 g) obtained above wasrecrystallized from 450 ml of ethanol according to the methods describedin Japanese Unexamined Patent Publication No. 191256/1990, and theresulting crystals were dried at 80° C. for 40 hours to obtain anhydrousaripiprazole crystals. The yield was 29.4 g (98.0%).

The melting point (mp) of these anhydrous aripiprazole crystals was 140°C., which is identical to the melting point of the anhydrousaripiprazole crystals described in Japanese Unexamined PatentPublication No. 191256/1990.

Reference Example 2

The crude product of aripiprazole (6930 g) obtained in Reference Example1 was heat dissolved by heating in 138 liters of hydrous ethanol (watercontent 20% by volume) according to the method presented at the 4thJoint Japanese-Korean Symposium on Separation Technology, the solutionwas gradually (2-3 hours) cooled to room temperature, and then waschilled to near 0° C. The precipitated crystals were collected byfiltration, about 7200 g of aripiprazole hydrate (wet-state).

The wet-state aripiprazole hydrate crystals obtained above were dried at80° C. for 30 hours to obtain 6480 g (93.5%) of anhydrous aripiprazolecrystals. The melting point (mp) of these crystals was 139.5° C.

Further, the crystalline form of these crystals was colorless flake.

The water content of the crystals were confirmed by the Karl Fischermethod, the moisture value was 0.03%, thus the crystals were confirmedas anhydrous product.

Reference Example 3

The aripiprazole hydrate (820 g) in wet state obtained from ReferenceExample 2 was dried at 50° C. for 2 hours to obtain 780 g ofaripiprazole hydrate crystals. The moisture value of the crystals had amoisture value was 3.82% measured according to the Karl Fischer method.As shown in FIG. 6, thermogravimetric/differential thermal analysisrevealed endothermic peaks at 75.0, 123.5 and 140.5° C. Becausedehydration began near at 70° C., there was no clear melting point (mp)was observed.

As shown in FIG. 7, the powder x-ray diffraction spectrum ofaripiprazole hydrate obtained by this method exhibited characteristicpeaks at 2θ=12.6°, 15.1°, 17.4°, 18.2°, 18.7°, 24.8° and 27.5°.

The powder x-ray diffraction spectrum of this aripiprazole hydrate wasidentical to the powder x-ray diffraction spectrum of aripiprazolehydrate presented at the 4th Joint Japanese-Korean Symposium onIsolation Technology.

Reference Example 4

The aripiprazole hydrate crystals (500.3 g) obtained in ReferenceExample 3 were milled by using a sample mill (small size atomizer). Themain axis rotation rate was set to 12,000 rpm and the feed rotation rateto 17 rpm, and a 1.0 mm herringbone screen was used. Milling wasfinished in 3 minutes, and obtained 474.6 g (94.9%) of powder ofaripiprazole hydrate A.

The aripiprazole hydrate A (powder) obtained in this way had a meanparticle size of 20-25 μm. The melting point (mp) was undeterminedbecause dehydration was observed beginning near at 70° C.

The aripiprazole hydrate A (powder) obtained above exhibited an ¹H-NMR(DMSO-d₆, TMS) spectrum which was substantially identical to the ¹H-NMRspectrum shown in FIG. 2. Specifically, it had characteristic peaks at1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt,J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

The aripiprazole hydrate A (powder) obtained above had a powder x-raydiffraction spectrum which was substantially identical to the powderx-ray diffraction spectrum shown in FIG. 3. Specifically, it hadcharacteristic peaks at 2θ=12.6°, 15.4°, 17.3°, 18.0°, 18.6°, 22.5° and24.8°. This pattern is different from the powder x-ray spectrum ofunmilled aripiprazole hydrate shown in FIG. 7.

The aripiprazole hydrate A (powder) obtained above had infraredabsorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and784 cm⁻¹ on the IR (KBr) spectrum.

As shown in FIG. 1, the aripiprazole hydrate A (powder) obtained abovehad a weak peak at 71.3° C. in thermogravimetric/differential thermalanalysis and a broad endothermic peak (weight loss observedcorresponding to one molecule of water) between 60-120° C. which wasclearly different from the endothermic curve of unmilled aripiprazolehydrate (see FIG. 6).

It will be appreciated that other embodiments and uses will be apparentto those skilled in the art and that the invention is not limited tothese specific illustrative examples.

Example 1

The aripiprazole hydrate A (powder) (44.29 kg) obtained in the ReferenceExample 4 was dried at 100° C. for 18 hours by using a hot air dryer andfurther heated at 120° C. for 3 hours, to obtain 42.46 kg (yield; 99.3%)of Anhydrous Aripiprazole Crystals B. These Anhydrous AripiprazoleCrystals B had a melting point (mp) of 139.7° C.

The Anhydrous Aripiprazole Crystals B obtained above had an ¹H-NMRspectrum (DMSO-d₆, TMS) which was substantially identical to the ¹H-NMRspectrum shown in FIG. 4. Specifically, they had characteristic peaks at1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt,J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

The Anhydrous Aripiprazole Crystals B obtained above had a powder x-raydiffraction spectrum which was substantially the identical to the powderx-ray diffraction spectrum shown in FIG. 5. Specifically, they hadcharacteristic peaks at 2θ=11.0°, 16.6°, 19.3°, 20.3° and 22.1°.

The Anhydrous Aripiprazole Crystals B obtained above had remarkableinfrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173,960 and 779 cm⁻¹ on the IR (KBr) spectrum.

The Anhydrous Aripiprazole Crystals B obtained above exhibited anendothermic peak near about at 141.5° C. inthermogravimetric/differential thermal analysis. The AnhydrousAripiprazole Crystals B obtained above exhibited an endothermic peaknear about at 140.7° C. in differential scanning calorimetry.

Example 2 Receptor Binding at the 5-HT1A Receptor 1. Materials andMethods

1.1 Test Compound

7-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydrocarbostyril(aripiprazole) was used as test compound.

1.2 Reference Compounds

Serotonin (5-HT) and WAY-100635(N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)-cyclohexanecarboxamide,a 5-HT1A receptor antagonist, manufactured by RBI (Natick, Mass.) wereused as reference compounds.

1.3 Vehicle

Dimethyl sulfoxide (DMSO) manufactured by Sigma Chemical Co. (St. Louis,Mo.) was used as vehicle.

1.4 Preparation of Test and Reference Compounds

Test compound was dissolved in 100% dimethyl sulfoxide (DMSO) to yield100 μM stock solutions (final concentration of DMSO in all tubescontaining test compound was 1%, v/v). All other reference compoundswere prepared by the same method using double-distilled water ratherthan DMSO.

1.5 Experimental Procedure for the [³⁵S]GTP_(γ)S Binding Assay

Test and reference compounds were studied in triplicate at 10 differentconcentrations (0.01, 0.1, 1, 5, 10, 50, 100, 1000, 10000 and 50000 nM)for their effects upon basal [³⁵S]GTP_(γ)S binding to h5-HT1A CHO cellmembranes. Reactions were performed in 5 ml glass test tubes containing8 μl of test/reference drug mixed with 792 μl of buffer (25 mM Tris HCl,50 mM NaCl, 5 mM MgCl₂, 0.1 mM EGTA, pH=7.4) containing GDP (1 μM),[³⁵S]GTP_(γ)S (0.1 nM) and h5-HT1A CHO cell membranes (10 μgprotein/reaction; NEN Life Science Products, Boston, Mass.; catalog #CRM035, lot #501-60024, GenBank # X13556). Reactions proceeded for 60min at room temperature and were terminated by rapid filtration throughWhatman GF/B filter paper, using a Brandel harvester and 4×3 ml ice-coldbuffer washes. S radio-activity bound to the filter paper was measuredusing liquid scintillation counting (1272 Clinigamma, LKB/Wallach).

1.6 Experimental Procedure to Determine the Binding Affinity of TestCompound (Aripiprazole) at the h5-HT1A Receptor

Test compound was studied in triplicate at 10 different concentrations(0.01, 0.1, 1, 10, 50, 100, 500, 1000, 5000 and 10000 nM) to determineits displacement of [³H]8-OH-DPAT (1 nM; NEN Life Sciences; catalog #NET 929, lot #3406035, Specific Activity=124.9 Ci/mmol) binding toh5-HT1A receptors in CHO cell membranes (15-20 μg protein; NEN LifeScience Products, catalog # CRM035, lot #501-60024). Membranes (396 μl)were incubated in 5 ml glass tubes containing [³H]8-OH-DPAT (396 μl),test compound or vehicle (8 μl) and buffer A (50 mM Tris.HCl, 10 mMMgSO₄, 0.5 mM EDTA, 0.1% (w/v) ascorbic acid, pH=7.4). All assaysproceeded for 60 min at room temperature and were terminated by rapidfiltration through Whatman GF/B filter paper (presoaked in buffer B; 50mM Tris.HCl, pH=7.4), using a Brandel harvester and 4×1 ml ice-coldwashes with buffer B. Non-specific binding was determined in thepresence of 10 μM (+)8-OH-DPAT.

1.7 Parameters Determined

Serotonin (5-HT) is a full 5-HT1A receptor agonist which stimulatesincreases in basal [³⁵S]GTP_(γ)S binding to h5-HT1A receptors inrecombinant CHO cell membranes. The test compound was studied at 10concentrations to determine effects upon basal [³⁵S]GTP_(γ)S bindingrelative to that produced by 10 μM 5-HT. The relative potency (EC₅₀, 95%confidence interval) and intrinsic agonist activity (% of E_(max) for 10μM 5-HT) was calculated for each compound by computerized non-linearregression analysis of complete concentration-effect data. The bindingaffinity of test compound at the h5-HT1A receptor was determined by itsability to prevent [³H]8-OH-DPAT binding to CHO cell membranes thatexpress this receptor. Non-linear regression analysis of the competitionbinding data was used to calculate an inhibition constant (IC₅₀, 95%confidence interval), which is the concentration of test compound thatoccupies half of the h5-HT1A sites specifically bound by [³H]8-OH-DPAT.The affinity of h5-HT1A receptors for test compound (Ki, 95% confidenceinterval) was calculated by the equation,Ki=(IC₅₀)/(1+([[³H]8-OH-DPAT]/Kd), where the Kd for [³H]8-OH-DPAT ath5-HT1A=0.69 nM (NEN Life Sciences). All estimates of drug bindingaffinity, potency and intrinsic efficacy at the h5-HT1A receptor werecalculated using GraphPad Prism version 3.00 for Windows (GraphPadSoftware, San Diego, Calif.).

2. Results

The test compound and 5-HT produced concentration-dependent increasesabove basal [³⁵S]GTP_(γ)S binding. 1% DMSO tested alone had no effectupon basal or drug-induced [³⁵S]GTP_(γ)S binding.

The test compound (EC₅₀=2.12 nM), 5-HT (EC₅₀=3.67 nM), potentlystimulated basal [³⁵S]GTP_(γ)S binding. Potency and intrinsic agonistefficacy estimates were derived by non-linear regression analysis withcorrelation coefficients (r²)>0.98 in each case (Table 1). The testcompound exerted partial agonist efficacies in the 65-70% range.WAY-100635 produced no significant change (unpaired Student's t-test) inbasal [³⁵S]GTP_(γ)S binding at all concentrations tested (Table 1).WAY-100635 did, however, completely inhibit the effects of 5-HT and testcompound upon [³⁵S]GTP_(γ)S binding to h5-HT1A receptors in CHO cellmembranes (Table 2). Tables 1 and 2 are shown below.

The test compound demonstrated high affinity binding to h5-HT1Areceptors in CHO cell membranes (IC₅₀=4.03 nM, 95% confidenceinterval=2.67 to 6.08 nM; Ki=1.65 nM, 95% confidence interval=1.09 to2.48 nM).

TABLE 1 Potency (EC₅₀) and Intrinsic Agonist Efficacy (E_(max)) of Testcompound and Reference Drugs in a h5-HT1A [³⁵S]GTPγS CHO-cell MembraneBinding Assay. EC₅₀, nM (95% Confidence E_(max) Goodness of Fit DrugInterval) (% ± SEM) (r²) Test 2.12 68.13 ± 3.16 0.986 Compound (0.87 to5.16) 5-HT 3.67 98.35 ± 4.47 0.986 (1.56 to 8.63) WAY-100635 — — —

TABLE 2 Inhibitory Potency (IC₅₀) of WAY-100635 versus 1 μMConcentration of 5-HT and Test compound in a h5-HT1A [³⁵S]GTPγS CHO-cellMembrane Binding Assay. WAY-100635 Inhibition Potency, IC₅₀, nM (95%Confidence Goodness of Fit Drug Combination Interval) (r²) 5-HT +WAY-100635 217.1 0.988 (127.4 to 369.7) Test compound + 392.2 0.989WAY-100635 (224.1 to 686.2)

Example 3 Pharmacological Test

The forced swimming test proposed by Porsolt et al. (Porsolt, R. D. etal.: Arch. Int. Pharmacodyn., 229, 327-336, 1977) is widely used as toan experimental animal model for predicting the antidepressant activityin clinical settings. In this experimental model, a test mouse is put ina cylinder in which a suitable amount of water is contained, and theantidepressant action of a test drug is detected by measuring theimmobility time, as the indication, shown by the mouse. It was reportedthat the action of shortening the immobility time is correlated withclinically observed antidepressive action (Willner, P.:Psychopharmacology, 83: 1-16, 1984). The crisis of depression is closelyconcerned with lowering of serotonin 5-HT1A receptor neurotransmissionaction, and the present inventors have found the facts thatantidepressive action of antidepressants which affect to serotoninsystem can be detected more precisely using prolongation of theimmobility time performed with WAY-100635, which is a selectiveserotonin 5-HT1A receptor antagonist. The prolongation of the immobilitytime performed by WAY-100635 is defined as the indication. In thismanner, the antidepressive action of test antidepressants was determinedby taking the prolongation of immobility time performed by WAY-100635 inthe forced swimming test as the indication.

In a cylinder (diameter: 9 cm, height 20 cm), water was poured thereinup to the height of 9.5 cm, from the bottom, then a mouse of ICR strainis placed in the cylinder. After placing the mouse in the cylinder, animmobility time of 6 minutes is measured. During the test, the watertemperature is maintained at 23 to 24° C. A test drug is orallyadministered to the mouse at 1 or 2 hours before placing the mouse inthe water. WAY-100635 is administered subcutaneously to the mouse 30minutes before placing the mouse in the water.

During this test, aripiprazole is used in combination together withcitalopram, escitalopram, fluoxetine, venlafaxine or milnacipran.Following such combination administration, a decrease in the immobilitytime (the antidepressant activity) is observed in comparison with thecase of single use of each one of aripiprazole, citalopram,escitalopram, fluoxetine, venlafaxine or milnacipran, respectively.

Further, when aripiprazole is used in combination with citalopram,escitalopram, fluoxetine, venlafaxine or milnacipran, a decrease in theimmobility time (the antidepressant activity) is observed in comparisonto administration of the available atypical antipsychotic drugs such asolanzapine, quetiapine, risperidone in combination with citalopram,fluoxetine, venlafaxine or milnacipran.

Example 4 Formulation Examples

Several non-limiting formulation examples of aripiprazole,dehydroaripiprazole and other metabolites with serotonin reuptakeinhibitors are presented below.

Formulation Sample Example 1 Anhydrous Aripiprazole Crystals B 5 mgFluoxetine 20 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mgTotal 220 mg

According to a preparation method which is well-known to a person havingan ordinary skill in the art, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 2 Anhydrous Aripiprazole Crystals B 5 mgDuloxetine 20 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mgTotal 220 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 3 Anhydrous Aripiprazole Crystals B 5 mgVenlafaxine 75 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mgTotal 275 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 4 Anhydrous Aripiprazole Crystals B 5 mgMilnacipran 50 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mgTotal 250 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 5 Anhydrous Aripiprazole Crystals B 5 mgCitalopram 20 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mgTotal 220 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 6 Anhydrous Aripiprazole Crystals B 5 mgFluvoxamine 50 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mgTotal 250 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 7 Anhydrous Aripiprazole Crystals B 5 mgParoxetine 20 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mgTotal 220 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 8 Anhydrous Aripiprazole Crystals B 5 mgSertraline 50 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mgTotal 250 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 9 Anhydrous Aripiprazole Crystals B 5 mgEscitalopram 10 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mgTotal 210 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Several non-limiting formulation examples of dehydroaripiprazole andserotonin reuptake inhibitors are presented below. It is to beunderstood that any one of DM-1458, DM-1451, DM-1452, DM-1454 or DCPP,as shown in FIG. 8, could be substituted for dehydroaripiprazole inthese disclosed formulations.

Formulation Sample Example 10 Dehydroaripiprazole 5 mg Fluoxetine 20 mgStarch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 220 mg

According to a preparation method which is well-known to a person havingan ordinary skill in the art, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 11 Dehydroaripiprazole 5 mg Duloxetine 20 mgStarch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 220 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 12 Dehydroaripiprazole 5 mg Venlafaxine 75 mgStarch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 275 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 13 Dehydroaripiprazole 5 mg Milnacipran 50 mgStarch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 250 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 14 Dehydroaripiprazole 5 mg Citalopram 20 mgStarch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 220 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 15 Dehydroaripiprazole 5 mg Fluvoxamine 50 mgStarch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 250 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 16 Dehydroaripiprazole 5 mg Paroxetine 20 mgStarch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 220 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 17 Dehydroaripiprazole 5 mg Sertraline 50 mgStarch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 250 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Formulation Sample Example 18 Dehydroaripiprazole 5 mg Escitalopram 10mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 210 mg

According to a common method, the tablet containing the above mentionedformulation was prepared.

Example 5

Method of Treatment of Patients Diagnosed with Major Depressive DisorderWho were Previously Non-Responsive or Partially Responsive toAnti-Depressant Medication

Aripiprazole is evaluated as an augmentation therapy in depressedpatients with major depressive disorder who were previouslynon-responsive or partially responsive to anti-depressant medicationcomprising serotonin reuptake inhibitors. These patients currentlyreceive therapy through administration of serotonin reuptake inhibitors.

Patients ranging in age from 18 to 65 years who have been diagnosed withmajor depressive disorder and are receiving therapy with a serotoninreuptake inhibitor are evaluated to ensure that they have a baselineHamilton score for depression (item 17) of 14 or higher. Only patientswith such Hamilton scores receive treatment. These patients areinterviewed to obtain a complete medical and psychiatric history.Aripiprazole is first administered at a dose of 10 mg/day and increasedto 30 mg/day as needed in the opinion of the monitoring psychiatrist.Aripiprazole is administered to these patients at a dose of from 10mg/day to 30 mg/day for a period of at least four weeks, and up to eightweeks for patients who respond well to this treatment during the firstfour weeks.

An improvement in alleviation of symptoms of depression is observed inthese patients following administration of aripiprazole as shown byresults of testing performed during and after the duration ofaripiprazole administration. The Hamilton test for depression and othermeasures such as clinical global impression (CGI), abnormal involuntarymovement scale (AIMS), Simpson Angus scale (SAS), and Barnes akathesiascale (Barnes), commonly known to one of ordinary skill in the art, areadministered to these patients.

Example 6

Method of Treatment of Patients with a New Diagnosis of Major DepressiveDisorder

A combination of aripiprazole and at least one serotonin reuptakeinhibitor is evaluated as a therapy for depression in patients newlydiagnosed with major depressive disorder. Patients ranging in age from18 to 65 years who are diagnosed with major depressive disorder areevaluated to ensure that they have a baseline Hamilton score fordepression (item 17) of 14 or higher. Only patients with this Hamiltonscore receive treatment. These patients are interviewed to obtain acomplete medical and psychiatric history. Aripiprazole is firstadministered at a dose of 10 mg/day and increased to 30 mg/day as neededin the opinion of the monitoring psychiatrist. Aripiprazole isadministered to these patients at a dose of from 10 mg/day to 30 mg/dayfor a period of at least four weeks, and up to eight weeks for patientswho respond well to this treatment during the first four weeks. Thearipiprazole is administered together with at least one serotoninreuptake inhibitor, wherein the serotonin reuptake inhibitor isfluoxetine, duloxetine, venlafaxine, milnacipran, citalopram,fluvoxamine, paroxetine or sertraline. The dosages to be used for theseserotonin reuptake inhibitors are provided elsewhere in this patentapplication.

The aripiprazole can be administered in one dosage form, for example atablet, and the serotonin reuptake inhibitor may be administered in aseparate one dosage form, for example a tablet. The administration mayoccur at about the same time or at different times during the day.

Alternatively, a dosage form containing aripiprazole in combination withat least one serotonin reuptake inhibitor may be administered. Suchcombinations include without limitation the following:aripiprazole/fluoxetine, aripiprazole/duloxetine,aripiprazole/venlafaxine, aripiprazole/milnacipran,aripiprazole/citalopram, aripiprazole/fluvoxamine,aripiprazole/paroxetine, and aripiprazole/sertraline. A preferredembodiment comprises a combination of aripiprazole and citalopram.

An improvement in alleviation of symptoms of depression is observed inthese patients following administration of aripiprazole and the one ormore serotonin reuptake inhibitors as shown by results of testingperformed during and after the duration of aripiprazole and serotoninreuptake inhibitor administration. The Hamilton test for depression andother measures such as CGI, AIMS, SAS, Simpson & Angus and Barnes,commonly known to one of ordinary skill in the art, are administered tothese patients. Results demonstrate an alleviation of the symptoms ofdepression.

Example 7

Method of Treatment of Patients Diagnosed with Major Depressive DisorderWho were Previously Non-Responsive or Partially Responsive toAnti-Depressant Medication

Dehydroaripiprazole, an active metabolite of aripiprazole, is evaluatedas an augmentation therapy in depressed patients with major depressivedisorder who were previously non-responsive or partially responsive toanti-depressant medication comprising serotonin reuptake inhibitors.These patients currently receive therapy through administration ofserotonin reuptake inhibitors.

Patients ranging in age from 18 to 65 years who have been diagnosed withmajor depressive disorder and are receiving therapy with a serotoninreuptake inhibitor are evaluated to ensure that they have a baselineHamilton score for depression (item 17) of 14 or higher. Only patientswith such Hamilton scores receive treatment. These patients areinterviewed to obtain a complete medical and psychiatric history.Dehydroaripiprazole is first administered at a dose of 10 mg/day andincreased to 30 mg/day as needed in the opinion of the monitoringpsychiatrist. Dehydroaripiprazole is administered to these patients at adose of from 10 mg/day to 30 mg/day for a period of at least four weeks,and up to eight weeks for patients who respond well to this treatmentduring the first four weeks.

An improvement in alleviation of symptoms of depression is observed inthese patients following administration of aripiprazole as shown byresults of testing performed during and after the duration ofaripiprazole administration. The Hamilton test for depression and othermeasures such as clinical global impression (CGI), abnormal involuntarymovement scale (AIMS), Simpson Angus scale (SAS), and Barnes akathesiarating scale (BARS), commonly known to one of ordinary skill in the art,are administered to these patients.

Example 8

Method of Treatment of Patients with a New Diagnosis of Major DepressiveDisorder

A combination of dehydroaripiprazole and at least one serotonin reuptakeinhibitor is evaluated as a therapy for depression in patients newlydiagnosed with major depressive disorder. Patients ranging in age from18 to 65 years who are diagnosed with major depressive disorder areevaluated to ensure that they have a baseline Hamilton score fordepression (item 17) of 14 or higher. Only patients with this Hamiltonscore receive treatment. These patients are interviewed to obtain acomplete medical and psychiatric history. Dehydroaripiprazole is firstadministered at a dose of 10 mg/day and increased to 30 mg/day as neededin the opinion of the monitoring psychiatrist. Dehydroaripiprazole isadministered to these patients at a dose of from 10 mg/day to 30 mg/dayfor a period of at least four weeks, and up to eight weeks for patientswho respond well to this treatment during the first four weeks. Thedehydroaripiprazole is administered together with at least one serotoninreuptake inhibitor, wherein the serotonin reuptake inhibitor isfluoxetine, duloxetine, venlafaxine, milnacipran, citalopram,fluvoxamine, paroxetine or sertraline.

The dehydroaripiprazole can be administered in one dosage form, forexample a tablet, and the serotonin reuptake inhibitor may beadministered in a separate one dosage form, for example a tablet. Theadministration may occur at about the same time or at different timesduring the day.

Alternatively, a dosage form containing dehydroaripiprazole incombination with at least one serotonin reuptake inhibitor may beadministered. Such combinations include without limitation thefollowing: dehydroaripiprazole/fluoxetine,dehydroaripiprazole/duloxetine, dehydroaripiprazole/venlafaxine,dehydroaripiprazole/milnacipran, dehydroaripiprazole/citalopram,dehydroaripiprazole/fluvoxamine, dehydroaripiprazole/paroxetine, anddehydroaripiprazole/sertraline. A preferred embodiment comprises acombination of dehydroaripiprazole and citalopram.

An improvement in alleviation of symptoms of depression is observed inthese patients following administration of dehydroaripiprazole and theone or more serotonin reuptake inhibitors as shown by results of testingperformed during and after the duration of dehydroaripiprazole andserotonin reuptake inhibitor administration. The Hamilton test fordepression and other measures such as CGI, AIMS, SAS, Simpson & Angusand Barnes, commonly known to one of ordinary skill in the art, areadministered to these patients. Results demonstrate an alleviation ofthe symptoms of depression.

All patents, patent applications, scientific and medical publicationsmentioned herein are hereby incorporated in their entirety. It should beunderstood, of course, that the foregoing relates only to preferredembodiments of the present invention and that numerous modifications oralterations may be made therein without departing from the spirit andthe scope of the invention as set forth in the appended claims.

Example 9 Pharmacological Test

The tail suspension test (TST) was originally described by Steru et al.(1985).¹⁾ A mouse suspended by its tail shows periods of agitation andimmobility. The antidepressant activity of a test drug can be detectedas an index of shortening the immobility time. This test is widely usedas to an experimental animal model for predicting the antidepressantactivity of a test drug in clinical settings. An automated device forperforming the TST was developed by the authors of the TST (1989).²⁾ Weimproved this device and developed our own device incorporating anelectric balance, an A/D converter, a testing box (30×25×25 cm), and apersonal computer. The mouse was suspended from a hook hanging from theceiling in the testing box by adhesive tape applied 20 mm from the tipof the tail. The duration of immobility was measured by the computer fora period of 15 min following the start of suspension. The immobilitytime for a period of 10 min (5-15 min) was evaluated. The experimentswere carried out in a sound-proof room.

Aripiprazole was suspended in 0.5% gum arabic-0.9% saline solution andcitalopram was dissolved in 0.9% saline solution. Aripiprazole (3 mg/kg)and citalopram (3 mg/kg) were orally administered to mice 60 min beforethe start of suspension. In this test, the decrease in the immobilitytime of the combination of aripiprazole with citalopram wasstatistically significant synergistic effect in comparison with theeffects of aripiprazole- and citaroplam-treated groups (Table 3).

REFERENCES

-   1) Steru L. et al.: The tail suspension test: A new method for    screening antidepressants in mice. Psychopharmacology 85, 367(1985).-   2) Steru L. and Porsolt R. D.: The automated tail suspension test: A    computerized device for evaluating psychotropic activity profiles.    Jpn J Clin Pharmacol Ther 20, 77(1989).

TABLE 3 Effects of aripiprazole and citalopram on duration of immobilityin the tail suspension test in mice Dose Immobility % of (mg/kg, time(sec, shortening for Drug p.o.) mean ± SE) immobility time Vehicle —499.2 ± 13.6 — Aripiprazole 3 486.4 ± 12.3 3 (Aripi.) Citalopram 3 468.7± 24.2 6 (Citalo.) Aripi. + Citalo. 3 + 3    380.6 ± 19.2**^(##$) 24  N= 7-9, **p < 0.01 vs. vehicle group (two-tailed t-test), ^(##)p < 0.01vs. aripiprazole alone (two-tailed t-test), ^($)p < 0.05 vs. citalopramalone (two-tailed t-test). The decrease in the immobility time of thecombination of aripiprazole with citalopram was a statisticallysignificant synergistic effect in comparison with the effects ofaripiprazole- and citaroplam-treated groups (p < 0.05, one-way ANOVA).

1-36. (canceled)
 37. A pharmaceutical composition comprising at leastone carbostyril derivative selected from the group consisting ofDM-1458, DM-1454 and DCPP in combination with at least one serotoninreuptake inhibitor.
 38. The composition of claim 37, wherein at leastone serotonin reuptake inhibitor is selected from the group consistingof fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram,fluvoxamine, paroxetine, sertraline, escitalopram and salts thereof. 39.The composition of claim 38, wherein at least one serotonin reuptakeinhibitor is citalopram.
 40. The composition of claim 37, furthercomprising at least one pharmaceutically acceptable carrier.
 41. Amethod of treating a subject afflicted with a mood disorder comprising:administering to the subject a pharmaceutical composition comprising atleast one carbostyril derivative selected from the group consisting ofDM-1458, DM-1454 and DCPP in combination with at least one serotoninreuptake inhibitor.
 42. The method according to claim 41, wherein themood disorder is chosen from depression or major depressive disorder.43. The method according to claim 41, wherein the mood disorder ischosen from major depressive disorder, all mood disorders,schizoaffective disorder and dementia with depressive symptoms.
 44. Amethod of treating a subject afflicted with a mood disorder comprising:administering to the subject a pharmaceutical composition comprising atleast one carbostyril derivative selected from the group consisting ofDM-1458, DM-1454 and DCPP in combination with at least one serotoninreuptake inhibitor, wherein the mood disorder is chosen from majordepressive disorder, endogenous depression, melancholia, depression incombination with psychotic episodes, bipolar disorder with depressivephase, refractory depression, dementia of the Alzheimer's type withdepressive symptoms, Parkinson's disease with depressive symptom, seniledementia, mood disorder associated with cerebral blood vessels and mooddisorder following head injury.